JP2008504044A5

JP2008504044A5 -

Info

Publication number: JP2008504044A5
Application number: JP2007518705A
Authority: JP
Filing date: 2005-07-01
Publication date: 2008-07-17
Anticipated expiration: 2025-07-01

Claims

A method for identifying a molecule suitable for the treatment, prevention or alleviation of an inflammatory disease or pain, wherein the candidate molecule is the amino acid sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 5 or SEQ ID NO: 7, or at least 90% sequence identity thereto Determining whether it is an agonist or antagonist of a GPR86 polypeptide comprising a sequence having sex.

2. The method of claim 1, wherein the candidate molecule is exposed to a GPR86 polypeptide and it is determined whether the candidate molecule is an agonist or antagonist of the GPR86 polypeptide.

3. The method of claim 1 or 2, wherein the candidate molecule is exposed to a GPR86 polypeptide expressing cell.

GPR86 preferential G protein G _i is conjugate to that GPR86 contacting a cell containing the receptor with a candidate compound, and the level of GPCR sensitivity markers, such as cyclic AMP (cAMP) in said cell of said contact 4. The method of claim 1, 2 or 3, wherein the agonist is identified by measuring whether the result is reduced.

GPR86 preferential G protein G _i is conjugate to that GPR86 contacting a cell containing the receptor with a candidate compound, and the level of GPCR sensitivity markers, such as cyclic AMP (cAMP) in said cell of said contact 4. The method of claim 1, 2 or 3, wherein the antagonist is identified by measuring whether the result increases.

_Contacting a cell containing a GPR86 receptor conjugated to a promiscuous G protein such as _Gα16 with a candidate compound, and the level of a GPCR sensitive marker such as cyclic AMP (cAMP) in the cell 4. The method of claim 1, 2 or 3, wherein an agonist is identified by measuring whether or not increases as a result of the contact.

_Contacting a cell containing a GPR86 receptor conjugated to a promiscuous G protein such as _Gα16 with a candidate compound, and the level of a GPCR sensitive marker such as cyclic AMP (cAMP) in the cell 4. The method of claim 1, 2 or 3, wherein an antagonist is identified by measuring whether or not is reduced as a result of the contact.

A nucleic acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 4 or a sequence having at least 90% sequence identity for identifying a molecule suitable for the treatment, prevention or alleviation of an inflammatory disease or pain Use of a GPR86 polynucleotide comprising.

(a) providing a wild-type animal or a transgenic non-human animal having a functionally disrupted endogenous GPR86 gene;
(b) exposing the wild-type animal or transgenic non-human animal to a candidate molecule; and
(c) measuring whether the biological parameter of the animal has changed as a result of the contact, wherein the biological parameter is a response to a stimulus, a response to heat, a response to light, 9. A method or use according to claim 1 or 8, selected from the group consisting of an immune response, an inflammatory response and a response to pain.

A method for identifying an agonist or antagonist of a GPR86 polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 5 or SEQ ID NO: 7 or a sequence having at least 90% sequence identity thereto, wherein the candidate molecule is a non-human animal And (a) altered pain sensitivity, which is increased or decreased pain sensitivity, and (b) increased or decreased compared to a wild-type animal that has not been administered the candidate molecule Determining whether or not the subject exhibits altered inflammatory pain sensitivity that is inflammatory pain sensitivity.

12. The method of claim 10, wherein the non-human animal expresses a functional GPR86 polypeptide.

The method according to claim 10 or 11, wherein the non-human animal is a wild-type animal.

13. A method according to claim 10, 11 or 12, wherein the non-human animal is a rodent.

The method according to any one of claims 10 to 13, wherein the non-human animal is a mouse.

15. The discrimination according to any one of claims 10 to 14, wherein the discrimination is performed using a tail flick test, a formalin test, a von Frey hair test, or a neuropathic pain test. Method.

A method for providing an index useful for diagnosing an inflammatory disease or pain in an individual or discriminating sensitivity to an inflammatory disease or pain, comprising: SEQ ID NO: 3 or SEQ ID NO: 5 or SEQ ID NO: 7 in a sample derived from the individual Detecting the change in expression pattern or expression level of a GPR86 polypeptide having the described amino acid sequence or a sequence having at least 90% sequence identity thereto.

A method for providing an index useful for diagnosing an inflammatory disease or pain in an individual or discriminating sensitivity to an inflammatory disease or pain, comprising: SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 4 in a sample derived from the individual Detecting the polymorphism in the GPR86 polynucleotide comprising the described nucleic acid sequence or a sequence having at least 90% sequence identity thereto.

18. A method or use according to any one of claims 1 to 17, wherein the agonist or antagonist comprises an immunoglobulin or an antibody.

The immunoglobulin or antibody is capable of specifically binding to a GPR86 polypeptide having the amino acid sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 5 or SEQ ID NO: 7 or a sequence having at least 90% sequence identity thereto; 19. A method or use according to claim 18.

GPR86 polypeptide agonist or antagonist comprising the amino acid sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 5 or SEQ ID NO: 7 or a sequence having at least 90% sequence identity thereto for the treatment or alleviation of inflammatory diseases or pain Use of a transgenic non-human animal having a functionally disrupted endogenous GPR86 gene or an isolated cell or tissue thereof, wherein the GPR86 gene is SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 4 Or a portion thereof or a sequence having at least 90% sequence identity thereto.

21. Use according to claim 20, wherein the transgenic non-human animal has a deletion in the GPR86 gene or a portion thereof.

When measured in a tail flick test, formalin test, von Frey hair test or neuropathic pain test, the transgenic non-human animal is compared to a wild type animal, The use according to claim 20 or 21, wherein (a) an altered pain sensitivity that is increased or decreased pain sensitivity, and (b) an altered inflammatory pain sensitivity that is increased or decreased inflammatory pain sensitivity. .

23. Use according to claim 20, 21 or 22, wherein the transgenic non-human animal is a mouse.

24. Use according to claim 23, wherein the transgenic non-human animal comprises a functionally disrupted GPR86 gene.

The transgenic non-human animal comprises a deletion in the GPR86 gene, the GPR86 gene comprising a nucleic acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 4 or a sequence having at least 90% sequence identity thereto; 25. Use according to claim 24.

26. Use of a non-human animal or isolated cell or tissue thereof according to any one of claims 20 to 25 as a model for inflammatory diseases or pain.

GPR86 having the amino acid sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 5 or SEQ ID NO: 7 or a sequence having at least 90% sequence identity in the preparation of a pharmaceutical composition for treating an inflammatory disease or pain in an individual Use of an agonist or antagonist of a polypeptide.

Pain is due to distant pain, injury, disease including acute pain, chronic pain, skin pain, somatic pain, visceral pain, myocardial ischemia, phantom pain, and neuropathic pain (neuralgia) Pain, headache, migraine, cancer pain, pain caused by neurological disorders such as Parkinson's disease, spinal and peripheral nerve surgery, brain tumor, traumatic brain injury (TBI), spinal cord trauma, chronic pain syndrome, chronic fatigue syndrome Pain, trigeminal neuralgia, glossopharyngeal neuralgia, postherpetic neuralgia and causalgia, lupus, sarcoidosis, arachnoiditis, arthritis, rheumatic disease, menstrual pain, back pain, low back pain, joint pain, abdominal pain, chest pain, labor pain, 28. The method or use according to any one of claims 1 to 27, selected from the group consisting of pain caused by any of skeletal muscle disease and skin disease, head trauma, and fibromyalgia.

Inflammatory disease is an inflammatory disease (e.g. rheumatoid arthritis, multiple sclerosis, Guillain-Barre syndrome, Crohn's disease, ulcerative colitis, psoriasis, graft-versus-host rejection, systemic lupus erythematosus or insulin-dependent diabetes) , Autoimmune diseases (e.g. toxic shock syndrome, osteoarthritis, diabetes or inflammatory bowel disease), acute pain, chronic pain, neuropathic pain, contact dermatitis, atherosclerosis, glomerulonephritis, reperfusion Disorders, bone resorption disorders, asthma, stroke, myocardial infarction, burns, adult respiratory distress syndrome (ARDS), multiple organ disorders secondary to trauma, skin disease with acute inflammatory components, acute suppurative meningitis, necrotizing enterocolitis Syndrome associated with hemodialysis, septic shock, leukopheresis, granulocyte transfusion, acute or chronic inflammation of the lung caused by smoke inhalation, endometriosis, Behcet's disease, uvea Inflammation, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer's disease, traumatic arthritis, sepsis, chronic obstructive pulmonary disease, congestive heart failure, osteoporosis, cachexia 29. A method according to any one of claims 1 to 28, selected from the group consisting of Parkinson's disease, periodontal disease, gout, allergic disease, age-related macular degeneration, infection and cystic fibrosis use.

30. An amino acid sequence as set forth in SEQ ID NO: 3 or SEQ ID NO: 5 or SEQ ID NO: 7 or a sequence having at least 90% sequence identity identified by the method or use according to any one of claims 1-29. A GPR86 polypeptide agonist or antagonist comprising.

Use of a molecule according to claim 30 for the treatment, prevention or alleviation of inflammatory diseases or pain.

GPR86 polypeptide comprising a kit for diagnosing inflammatory disease or pain or susceptibility thereto, comprising the amino acid sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 5 or SEQ ID NO: 7 or a sequence having at least 90% sequence identity thereto Or a part thereof, an antibody against said GPR86 polypeptide, or any one or more of nucleic acids capable of encoding such a kit.

A pharmaceutical composition for treating an individual suffering from an inflammatory disease or pain, comprising the amino acid sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 5 or SEQ ID NO: 7 or a sequence having at least 90% sequence identity thereto The pharmaceutical composition comprising a GPR86 polypeptide, an agonist of the GPR86 polypeptide, or an antagonist of the GPR86 polypeptide.